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Enabling Systems Genetics to Translational Medicine:
The PATO approach
George Gkoutos
Department of GeneticsUniversity of Cambridge
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Exploring the Phenome
Key EU/NIH missions:
– integration and analysis of disease data within and across species diagnostic and therapeutic advances at the clinical level
– identification of causative genes for Mendelian orphan diseases
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Power of the Phenotype
The meaningful cross species translation of phenotype is essential phenotype-driven gene function discovery and comparative pathobiology
Goal - “A platform for facilitating mutual understanding and interoperability of phenotype information across species and domains of knowledge amongst people and machines” …..
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Phenotype And Trait Ontology (PATO)
• phenotypes may be described in many different dimensions, e.g.– the biochemical ('alcohol dehydrogenase null')– the cellular ('cell division arrested at metaphase’)– the anatomical ('eye absent')– the behavioral (‘hyperactive’)– etc.
• in whatever dimension and granularity, however, there is a commonality so that phenotypic descriptions can be decomposed into two parts
– An entity that is affected. This entity may be an enzyme, an
anatomical structure or a complex biological process.
– The qualities of that entity.
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Type and Sources
• Type of data
Behaviour and cognition, Clinical chemistry and haematology, Hormonal and Metabolic Systems, Cardiovascular, Allergy and Infectious diseases, Sensory Systems, Central/Peripheral Nervous and Skeletal Muscle Systems, Cancer Phenotyping, Bone, Cartilage, Arthritis, Osteoporosis, Necropsy Exam, Pathology, Histology, etc. etc. etc.
• Source of phenotype information–Literature–Experimental data–Various representation methodologies–Complex phenotype data
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PATO today
PATO is now being used as a community standard for phenotype description – many consortia (e.g. Phenoscape, The Virtual
Human Physiology project (VPH), IMPC, BIRN, NIF) – most of the major model organism databases,
(e.g. example Flybase, Dictybase, Wormbase, Zfin, Mouse genome database (MGD))
– international projects
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PATO’s Semantic Framework
• Conceptual Layer• Semantic Components Layer• Unification Layer• Formalisation Layer• Integration Layer
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PATO’s Conceptual Layer
PATOSpecies Independent
Core Ontologies(e.g. anatomy, biological
process, chemistry)
EQ Phenotype Description
Entity (E) Quality (Q)
PATOSpecies Independent
EQ Phenotype Description
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Mouse Body weight
PATOSpecies Independent
Mouse Anatomy (MA)
EQ Phenotype Description
Body(E) Weight(Q)
PATOSpecies Independent
EQ mouse body weight
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Semantic Components Layer
• Behavior– NeuroBehavior Ontology– Behavioral Phenotype Ontology
• Pathology• Physiology– Cerebellar ataxiaCreate links to behavioral observation to physiology
manifestations• Cell Phenotype• Quantitative measurement (Units Ontology)
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PATO’s Unification Layer
Following the GO paradigm, several examples of attempts to formalize species specific phenotype description have been adopted:e.g. Mammalian Phenotype Ontology (MP), Plant & Trait Ontology, Human Phenotype Ontology (HPO), etc.
• Advantages–Easy for annotation–Control–Complex phenotypic information
• Disadvantages– lack of rigidity e.g. quantitative data– ontology management e.g. expansion– incapable of bridging different phenotype descriptions (for either the
same or separate species)
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HELLP syndrome
HELLP syndrome
Liver failureLiver failureHepatic failureHepatic failure
Pregnancy related premature deathPregnancy related premature death
Glomerular vascular disorder
Glomerular vascular disorderAbnormal
glomeruliAbnormal glomeruli
HypertensionHypertension HypertensionHypertension
ThrombocytopeniaThrombocytopenia ThrombocytopeniaThrombocytopenia
Renal FailureRenal Failure Renal failureRenal failure
Hepatic necrosisHepatic necrosis
Acute and subacute liver necrosis
Acute and subacute liver necrosis
ProteinuriaProteinuria ProteinuriaProteinuria
Haemolytic anaemia
Haemolytic anaemia
Anaemia haemolyticAnaemia
haemolytic
HPOMP
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PATO-based definitions
Aristotelian definitions (genus-differentia)
A <Q> *which* inheres_in an <E>
[Term] id: MP:0001262 name: decreased body weightnamespace: mammalian_phenotype_xpSynonym: low body weightSynonym: reduced body weightdef: " lower than normal average weight “[] is_a: MP:0001259 ! abnormal body weightintersection_of: PATO:0000583 ! decreased weightintersection_of: inheres_in MA:0002405 ! adult mouse
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HELLP syndrome
HELLP syndrome
Liver failureLiver failureHepatic failureHepatic failure
Pregnancy related premature deathPregnancy related premature death
Glomerular vascular disorder
Glomerular vascular disorderAbnormal
glomeruliAbnormal glomeruli
HypertensionHypertension HypertensionHypertension
ThrombocytopeniaThrombocytopenia ThrombocytopeniaThrombocytopenia
Renal FailureRenal Failure Renal failureRenal failure
Hepatic necrosisHepatic necrosis
Acute and subacute liver necrosis
Acute and subacute liver necrosis
ProteinuriaProteinuria ProteinuriaProteinuria
Haemolytic anaemia
Haemolytic anaemia
Anaemia haemolyticAnaemia
haemolytic
HPOMP
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HELLP syndrome
HELLP syndrome
Liver failureLiver failureHepatic failureHepatic failure
Pregnancy related premature deathPregnancy related premature death
Glomerular vascular disorder
Glomerular vascular disorderAbnormal
glomeruliAbnormal glomeruli
HypertensionHypertension E: Blood (MA)Q: Increased pressure (PATO)
HypertensionHypertensionE: Blood (FMA)Q: Increased pressure (PATO)
ThrombocytopeniaThrombocytopeniaE: Platelet(CL)Q: Decreased number (PATO)
ThrombocytopeniaThrombocytopeniaE: Platelet (CL)Q: Decreased number (PATO)
Renal FailureRenal FailureE: Renal system process (GO)Q: disfunctional (PATO)
Renal failureRenal failureE: Renal system process (GO)Q: disfunctional (PATO)
Hepatic necrosisHepatic necrosis
E: Liver (MA)Q: Necrosis (MPATH)
Acute and subacute liver necrosis
Acute and subacute liver necrosis
E: Liver (FMA)Q:Necrotic (PATO)
ProteinuriaProteinuria ProteinuriaProteinuria
Haemolytic anaemia
Haemolytic anaemia
Anaemia haemolyticAnaemia
haemolytic
E: Hepatocobiliary system process (GO)Q: disfunctional (PATO)
E: Hepatocobiliary system process (GO)Q: disfunctional (PATO)
E: Glomerulus (MA)Q: abnormal ( PATO)
E: Glomerulus (FMA)Q: abnormal ( PATO)
E: Urine(MA)Q: Increased concentrationE2:Protein( CheBI)
E: Urine(FMA)Q: Increased concentrationE2:Protein( CheBI)
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Progress to date
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Comparative Phenomics
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PATO Conceptual Layer
EQ
EQ Modellink Entities (E) from GO, CheBI, FMA etc. to Qualities (Q) from PATO
EQ statements
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Semantic Components Layer
EQ
• Behavior• Pathology• Physiology• UBERON• Cell Phenotype• Measurements(Units Ontology)
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Unification Layer
Provision of PATO based equivalence definitions
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UBERON-Integrating Species-Centric Anatomies
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Formalisation Layer
transform OWL ontologies into OWL EL enable tractable reasoning
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Integration Layer
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Cross Species Data Integration
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Cross species integration framework
• A PATO-based cross species phenotype network based on experimental phenotype data for 5 model organisms yeast, fly, worm, fish, mouse and human
• integration of anatomy and phenotype ontologies– exploit through OWL reasoning– more than 500,000 classes and 1,500,000 axioms• PhenomeNET forms a network with more than
111.000 complex phenotype nodes representing complex phenotypes
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PhenomeNet
• quantitative evaluation based on predicting orthology, pathway, disease
• Receiver Operating Characteristic (ROC) Curve analysis• Area Under Curve (AUC) = 0.7
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E1: Aorta(FMA)Q: overlap with (PATO)E2: Membranous part of the interventricular septum (FMA)
Candidate disease gene prioritization
• Predict all known human and mouse disease genes• Adam19 and Fgf15 mouse genes • using zebrafish phenotypes - mammalian homologues
of Cx36.7 and Nkx2.5 are involved in TOF
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• Enhance the network e.g.– Semantics e.g Behavior and pathology related phenotypes etc.– Methods e.g. text mining, machine learning etc.
• PhenomeNET now significantly outperforms previous phenotype-based approaches of predicting gene–disease associations
• Performance matches gene prioritization methods based on prior information about molecular causes of a disease
AUC = 0.9
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IRDiRC
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IRDiRCdbGAPdbGAP
dbSNPdbSNP
ClinVarClinVar
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Translational Research
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The power of phenotype
• Candidate disease gene prioritization • Copy number variations • Rare and orphan diseases • Functional validation of human variation
studies (e.g GWAS)• identification of pathogenicity of human
mutations• new therapeutic strategies
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Novel drug discovery and repurposing
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Phenotype-based drug discovery and repurposing
Variety of methods successfully being applied for drug repositioning and the suggestions of potentially novel drugs
Can a phenotype of gene which the drug interacts be used to predict diseases in which the drug is active?
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Results
AUC =
0.65 PharmGKB0.63 FDA0.69 CTD
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Future work
• integrated system for the analysis and prediction of drug–disease associations with emphasis on orphan diseases
• include other drug resources such DrugBank and CTD • combine them with other methods such as:
– drug response – gene expression profiles – drug–drug similarity– drug–disease similarity– text mining of known associations
• employ other computational approaches (machine learning approach, statistical testing, semantic similarity)
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Mathematical Modelling
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Model-based investigation of optimal cancer chemotherapy
• mathematical modelling of cancer progression and optimal cancer chemotherapy
• cancer dynamics, pharmacokinetic and drug-related toxicity models study the effect of widely used anti-cancer agents irinotecan (CPT-11) and 5-fluorouracil (5-FU)
• include drug related side-effects categorised in terms of undesirability of the side-effect as well as the frequency of appearance
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• models replicate animal data successfully • optimal administration: 5-FU CPT-11 • future directions
– experimental validation – specific cancer characteristics, drug resistance, metastasis and cell-cycle
b) Optimal controla) Model predictions alongiside experimental data
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RICORDO - Towards Physiology knowledge representation
• Virtual Physiology Human (VPH) - “A major challenge for the future how is to integrate physiology knowledge into robust and fully reliable computer models and "in silico" environments”
• The RICORDO approach (www.ricordo.eu)– ontology based framework for the description of VPH
models and data– connect distributed repositories with software tools– standardization of the minimal information content
• Goal - qualitative representation of physiology
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Translational Medicine
Personalised Medicine
Personalised Medicine
translation
Cros
s Sp
ecies
Inte
grati
on